TY - JOUR
T1 - Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence
AU - Cartwright, Rufus
AU - Franklin, Larissa
AU - Tikkinen, Kari A.O.
AU - Kalliala, Ilkka
AU - Miotla, Pawel
AU - Rechberger, Tomasz
AU - Offiah, Ifeoma
AU - McMahon, Steve
AU - O’Reilly, Barry
AU - Lince, Sabrina
AU - Kluivers, Kirsten
AU - Post, Wilke M.
AU - Poelmans, Geert
AU - Palmer, Melody R.
AU - Wessells, Hunter
AU - Wong, Andrew
AU - Kuh, Diana
AU - Kivimaki, Mika
AU - Kumari, Meena
AU - Mangino, Massimo
AU - Spector, Tim
AU - Guggenheim, Jeremy A.
AU - Lehne, Benjamin
AU - De Silva, N. G.Maneka
AU - Evans, David M.
AU - Lawlor, Debbie
AU - Karhunen, Ville
AU - Mannikko, Minna
AU - Marczak, Malgorzata
AU - Bennett, Phillip R.
AU - Khullar, Vik
AU - Jarvelin, Marjo Riitta
AU - Walley, Andrew
N1 - Publisher Copyright:
© 2021 by American Urological Association Education and Research, Inc.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Purpose: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence. Materials and Methods: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using AffymetrixÒ arrays with replication with TaqManÒ polymerase chain reaction. Results: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10-8). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure (MARCO) gene (replication p[0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 (EDN1) gene (replication p[0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001). Conclusions: We uncovered 2 new risk loci near the genes endothelin 1 (EDN1), associated with urgency incontinence, and macrophage receptor with collagenous structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.
AB - Purpose: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence. Materials and Methods: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using AffymetrixÒ arrays with replication with TaqManÒ polymerase chain reaction. Results: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10-8). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure (MARCO) gene (replication p[0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 (EDN1) gene (replication p[0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001). Conclusions: We uncovered 2 new risk loci near the genes endothelin 1 (EDN1), associated with urgency incontinence, and macrophage receptor with collagenous structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.
KW - genetics
KW - genome-wide association study
KW - genomics
KW - urinary incontinence, stress
KW - urinary incontinence, urge
UR - https://www.scopus.com/pages/publications/85114078648
U2 - 10.1097/JU.0000000000001822
DO - 10.1097/JU.0000000000001822
M3 - Article
C2 - 33904754
AN - SCOPUS:85114078648
SN - 0022-5347
VL - 206
SP - 679
EP - 687
JO - Journal of Urology
JF - Journal of Urology
IS - 3
ER -